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Abstract:

The present invention relates to pyrrolopyridone compounds of the formula
(I),
##STR00001##
salts thereof, to pharmaceutical compositions containing them and their
use in medicine. In particular, the invention relates to compounds as
activators of AMPK.

10. A compound of formula (I) or a salt thereof according to any claim 1
wherein the salt is a pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising a) a compound of formula (I)
or pharmaceutically acceptable salt thereof according to claim 10 and b)
at least one pharmaceutically acceptable carrier.

12-16. (canceled)

17. A method of treating a disease or a condition susceptible to
amelioration by an AMPK activator comprising administering to a subject a
therapeutically effective amount of a compound for formula (I) or a
pharmaceutically acceptable salt thereof according to claim 10.

[0003] More recently an involvement of AMPK in the regulation of not only
cellular but also whole body energy metabolism has become apparent. It
was shown that the adipocyte-derived hormone leptin leads to a
stimulation of AMPK and therefore to an increase in fatty acid oxidation
in skeletal muscle (Minokoshi, Y. et. al. Leptin stimulates fatty-acid
oxidation by activating AMP-activated protein kinase. Nature 415: 339
(2002)). Adiponectin, another adipocyte derived hormone leading to
improved carbohydrate and lipid metabolism, has been demonstrated to
stimulate AMPK in liver and skeletal muscle (Yamauchi, T. et. al.
Adiponectin stimulates glucose utilization and fatty acid oxidation by
activating AMP-activated protein kinase. Nature Medicine 8: 1288 (2002),
Tomas, E. et. al. Enhanced muscle fat oxidation and glucose transport by
ACRP30 globular domain: Acetyl-CoA carboxylase inhibition and
AMP-activated protein kinase activation. PNAS 99: 16309(2002)). The
activation of AMPK in these circumstances seems to be independent of
increasing cellular AMP levels but rather due to phosphorylation by one
or more yet to be identified upstream kinases.

[0004] Based on the knowledge of the above-mentioned consequences of AMPK
activation, certain beneficial effects could be expected from in vivo
activation of AMPK. In liver, decreased expression of gluconeogenic
enzymes could reduce hepatic glucose output and improve overall glucose
homeostasis, and both direct inhibition and/or reduced expression of key
enzymes in lipid metabolism could lead to decreased fatty acid and
cholesterol synthesis and increased fatty acid oxidation. Stimulation of
AMPK in skeletal muscle could increase glucose uptake and fatty acid
oxidation with resulting improvement of glucose homeostasis and, due to a
reduction in intra-myocyte triglyceride accumulation, to improved insulin
action. Finally, the increase in energy expenditure could lead to a
decrease in body weight. The combination of these effects in metabolic
syndrome could be expected to reduce the risk for acquiring
cardiovascular diseases.

[0005] Several studies in rodents support this hypothesis (Bergeron, R.
et. al. Effect of 5-aminoimidazole-4-carboxamide-1(beta)-D-ribofuranoside
infusion on in vivo glucose metabolism in lean and obese Zucker rats.
Diabetes 50:1076 (2001), Song, S. M. et. al.
5-Aminoimidazole-4-darboxamide ribonucleoside treatment improves glucose
homeostasis in insulin-resistant diabeted (ob/ob) mice. Diabetologia
45:56 (2002), Halseth, A. E. et. al. Acute and chronic treatment of ob/ob
and db/db mice with AICAR decreases blood glucose concentrations.
Biochem. and Biophys. Res. Comm. 294:798 (2002), Buhl, E. S. et. al.
Long-term AICAR administration reduces metabolic disturbances and lowers
blood pressure in rats displaying feature of the insulin resistance
syndrome. Diabetes 51: 2199 (2002)). Until recently most in vivo studies
have relied on the AMPK activator AICAR, a cell permeable precursor of
ZMP. ZMP acts as an intracellular AMP mimic, and, when accumulated to
high enough levels, is able to stimulate AMPK activity (Corton, J. M. et.
al. 5-Aminoimidazole-4-carboxamide ribonucleoside, a specific method for
activating AMP-activated protein kinase in intact cells? Eur. J. Biochem.
229: 558 (1995)). However, ZMP also acts as an AMP mimic in the
regulation of other enzymes, and is therefore not a specific AMPK
activator (Musi, N. and Goodyear, L. J. Targeting the AMP-activated
protein kinase for the treatment of Type 2 diabetes. Current Drug
Targets-Immune, Endocrine and Metabolic Disorders 2:119 (2002)). Several
in vivo studies have demonstrated beneficial effects of both acute and
chronic AICAR administration in rodent models of obesity and Type 2
diabetes (Bergeron, R. et. al. Effect of
5-aminoimidazole-4-carboxamide-1(beta)-D-ribofuranoside infusion on in
vivo glucose metabolism in lean and obese Zucker rats. Diabetes 50:1076
(2001), Song, S. M. et. al. 5-Aminoimidazole-4-darboxamide ribonucleoside
treatment improves glucose homeostasis in insulin-resistant diabetic
(ob/ob) mice. Diabetologia 45:56 (2002), Halseth, A. E. et. al. Acute and
chronic treatment of ob/ob and db/db mice with AICAR decreases blood
glucose concentrations. Biochem. and Biophys. Res. Comm. 294:798 (2002),
Buhl, E. S. et. al. Long-term AICAR administration reduces metabolic
disturbances and lowers blood pressure in rats displaying feature of the
insulin resistance syndrome. Diabetes 51: 2199 (2002)). For example, 7
week AICAR administration in the obese Zucker (fa/fa) rat leads to a
reduction in plasma triglycerides and free fatty acids, an increase in
HDL cholesterol, and a normalization of glucose metabolism as assessed by
an oral glucose tolerance test (Minokoshi, Y. et. al. Leptin stimulates
fatty-acid oxidation by activating AMP-activated protein kinase. Nature
415: 339 (2002)). In both ob/ob and db/db mice, 8 day AICAR
administration reduces blood glucose by 35% (Halseth, A. E. et. al. Acute
and chronic treatment of ob/ob and db/db mice with AICAR decreases blood
glucose concentrations. Biochem. and Biophys. Res. Comm. 294:798 (2002)).
In addition to AICAR, more recently it was found that the diabetes drug
metformin can activate AMPK in vivo at high concentrations (Zhou, G. et.
al. Role of AMP-activated protein kinase in mechanism of metformin
action. The J. of Clin. Invest. 108: 1167 (2001), Musi, N. et. al.
Metformin increases AMP-activated protein kinase activity in skeletal
muscle of subjects with Type 2 diabetes. Diabetes 51: 2074 (2002)),
although it has to be determined to what extent its antidiabetic action
relies on this activation. As with leptin and adiponectin, the
stimulatory effect of metformin is indirect via a mild inhibition of
mitochondrial respiratory chain complex 1 (Leverve X. M. et al.
Mitochondrial metabolism and type-2 diabetes: a specific target of
metformin. Diabetes Metab. 29: 6588 (2003)). In addition to pharmacologic
intervention, several transgenic mouse models have been developed in the
last years and initial results are becoming available. Expression of
dominant negative AMPK in skeletal muscle of transgenic mice has
demonstrated that the AICAR effect on stimulation of glucose transport is
dependent on AMPK activation (Mu, J. et. al. A role for AMP-activated
protein kinase in contraction and hypoxia-regulated glucose transport in
skeletal muscle. Molecular Cell 7: 1085 (2001)), and therefore likely not
caused by non-specific ZMP effects. Similar studies in other tissues will
help to further define the consequences of AMPK activation. It is
believed that pharmacologic activation of AMPK may have benefits in
relation to metabolic syndrome with improved glucose and lipid metabolism
and a reduction in body weight. To qualify a patient as having metabolic
syndrome, three out of the five following criteria must be met: elevated
blood pressure above 130/85 mmHg, fasting blood glucose above 110 mg/dl,
abdominal obesity above 40'' (men) or 35'' (women) waist circumference,
and blood lipid changes as defined by an increase in triglycerides above
150 mg/dl or decreased HDL cholesterol below 40 mg/dl (men) or 50 mg/dl
(women). Therefore, the combined effects that may be achieved through
activation of AMPK in a patient who qualifies as having metabolic
syndrome would raise the interest of this target.

[0006] Lowering of blood pressure has been reported to be a consequence of
AMPK activation (Buhl, E. S. et. al. Long-term AICAR administration
reduces metabolic disturbances and lowers blood pressure in rats
displaying feature of the insulin resistance syndrome. Diabetes 51: 2199
(2002)), therefore activation of AMPK might have beneficial effects in
hypertension. Through combination of some or all of the above-mentioned
effects stimulation of AMPK may to reduce the incidence of cardiovascular
diseases (e.g. MI, stroke). Increased fatty acid synthesis is a
characteristic of many tumor cells, therefore decreased synthesis of
fatty acids through activation of AMPK could be useful as a cancer
therapy (Huang X. et al. Important role of the LKB1-AMPK pathway in
suppressing tumorigenesis in PTEN-deficient mice. Biochem J. 412: 211
(2008). AMPK can also be considered as a metabolic tumor suppressor and
AMPK activators could be helpful in general cancer therapy (Luo Z. Et al.
AMPK as a metabolic tumor suppressor: control of metabolism and cell
growth. Future Oncol. 6: 457 (2010)). Stimulation of AMPK has been shown
to stimulate production of ketone bodies from astrocytes (Blazquez, C.
et. al. The AMP-activated protein kinase is involved in the regulation of
ketone body production by astrocytes. J. Neurochem. 73: 1674 (1999)), and
might therefore be a strategy to treat ischemic events in the brain.
Stimulation of AMPK has been shown to improve cognition and
neurodegenerative diseases in a mice model (Dagon Y. et al. Nutritional
status, cognition, and survival: a new role for leptin and AMP kinase. J.
Biol. Chem. 280:42142 (2005)). Stimulation of AMPK has been shown to
stimulate expression of uncoupling protein 3 (UCP3) in skeletal muscle
(Zhou, M. et. al. UCP-3 expression in skeletal muscle: effects of
exercise, hypoxia, and AMP-activated protein kinase. Am. J. Physiol.
Endocrinol. Metab. 279: E622 (2000)) and might therefore be a way to
prevent damage from reactive oxygen species. Endothelial NO synthase
(eNOS) has been shown to be activated through AMPK mediated
phosphorylation (Chen, Z.-P., et. al. AMP-activated protein kinase
phosphorylation of endothelial NO synthase. FEBS Letters 443: 285
(1999)), therefore AMPK activation may be used to improve local
circulatory systems. AMPK has also been described to directly affect
PGC-1alpha activity through phosphorylation and then regulate
mitochondria biogenesis (Jager S, et al. AMP-activated protein kinase
(AMPK) action in skeletal muscle via direct phosphorylation of
PGC-1alpha. Proc Natl Acad Sci 104:12017 (2007)). AMPK activation can be
then a way to treat mitochondrial disorders (e.g. sarcopenia and some
mitochondrial rare diseases). Recently, several reports describe
beneficial effect of AMPK activation on virus infection. While virus
infection is found to reduce AMPK activity in infected cells or tissues,
AMPK activation is proposed as a anti-viral therapy (Mankouri J. et al.,
Enhanced hepatitis C virus genome replication and lipid accumulation
mediated by inhibition of AMP-activated protein kinase, Proc Natl Acad
Sci 107: 11549 (2010)).

[0019] In another aspect, the present invention provides methods of
treating diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia,
obesity, hypertension, cerebral ischemia, cognitive defect and cancer
comprising administration of a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt thereof to
a subject in need thereof.

[0020] In another aspect, the present invention provides methods of
treating type 2 diabetes, obesity or dyslipidaemia comprising
administration of a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof to a subject in
need thereof.

[0021] In another aspect, the invention provides a compound of formula (I)
or a pharmaceutically acceptable salt thereof for use in human or
veterinary medical therapy.

[0023] In another aspect, the invention provides a compound of formula (I)
or a pharmaceutically acceptable salt thereof, for use in the treatment
of diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity,
hypertension, cerebral ischemia, cognitive defect and cancer.

[0024] In another aspect, the invention provides a compound of formula (I)
or a pharmaceutically acceptable salt thereof, for use in the treatment
type 2 diabetes, obesity or dyslipidaemia.

[0026] In another aspect, the invention provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament for the treatment of diabetes, metabolic
syndrome, atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral
ischemia, cognitive defect and cancer.

[0027] In another aspect, the invention provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof in the
manufacture of a medicament for the treatment of type 2 diabetes, obesity
or dyslipidaemia.

DESCRIPTION OF THE EMBODIMENTS

[0028] All aspects and embodiments of the invention described herein are
in respect of compounds of formula I and (IA) unless otherwise specified.

[0029] In one aspect of the invention, R1 represents --CN, H or
--CO2C1-3alkyl (such as --CO2C2H5).

[0030] In another aspect of the invention, R1 represents CN. In
another aspect of the invention, R1 represents H. In another aspect
of the invention, R1 represents --CO2C1-3alkyl. In another
aspect of the invention R1 represents --CO2C2H5.

[0031] In another aspect of the invention, R1 represents phenyl
optionally substituted by one or two groups independently selected from
--C1-4alkyl (such as --CH3), --OC1-4alkyl (such as
--OCH3 or --OC2H5), --OH, --C1-4haloalkyl (such as
--CF3), --NO2, --CN, --CO2H, --C(═O)NH2 or
halogen (such as chloro, bromo or fluoro).

[0032] In another aspect of the invention, R1 represents phenyl
optionally substituted by one or two groups independently selected from
--C1-4alkyl (such as --CH3), --OC1-4alkyl (such as
--OCH3), --OH, --C1-4haloalkyl (such as --CF3), --CN or
halogen (such as chloro, bromo or fluoro).

[0033] In another aspect of the invention, R1 represents phenyl
substituted by one or two groups independently selected from
--C1-4alkyl (such as --CH3), --OC1-4alkyl (such as
--OCH3 or --OC2H5), --OH, --C1-4haloalkyl (such as
--CF3), --NO2, --CN, --CO2H, --C(═O)NH2 or
halogen (such as chloro, bromo or fluoro).

[0034] In another aspect of the invention, R1 represents phenyl
substituted by one or two groups independently selected from
--C1-4alkyl (such as --CH3), --OC1-4alkyl (such as
--OCH3), --OH, --C1-4haloalkyl (such as --CF3), --CN or
halogen (such as chloro, bromo or fluoro).

[0035] In another aspect of the invention, R1 represents phenyl
optionally substituted by a group independently selected from
--C1-4alkyl (such as --CH3), --OC1-4alkyl (such as
--OCH3 or --OC2H5), --OH, --C1-4haloalkyl (such as
--CF3), --NO2, --CN, --CO2H, --C(═O)NH2 or
halogen (such as chloro, bromo or fluoro).

[0036] In another aspect of the invention, R1 represents phenyl
optionally substituted by a group selected from --C1-4alkyl (such as
--CH3), --OC1-4alkyl (such as --OCH3), --OH,
--C1-4haloalkyl (such as --CF3), --CN or halogen (such as
chloro, bromo or fluoro).

[0037] In another aspect of the invention, R1 represents phenyl
substituted by a group independently selected from --C1-4alkyl (such
as --CH3), --OC1-4alkyl (such as --OCH3 or
--OC2H5), --OH, --C1-4haloalkyl (such as --CF3),
--NO2, --CN, --CO2H, --C(═O)NH2 or halogen (such as
chloro, bromo or fluoro).

[0038] In another aspect of the invention, R1 represents phenyl
substituted by a group selected from --C1-4alkyl (such as
--CH3), --OC1-4alkyl (such as --OCH3), --OH,
--C1-4haloalkyl (such as --CF3), --CN or halogen (such as
chloro, bromo or fluoro).

[0039] In another aspect of the invention, R1 represents phenyl
optionally substituted by one group selected from --OC1-4alkyl (such
as --OCH3), --CN or halogen (such as chloro, bromo or fluoro).

[0040] In another aspect of the invention, R1 represents phenyl
substituted by a group selected from --OC1-4alkyl (such as
--OCH3), --CN or halogen (such as chloro, bromo or fluoro).

[0041] In another aspect of the invention, R1 represents phenyl
substituted by a group independently selected from --CH3,
--OCH3, --OC2H5, --OH, --CF3, --NO2, --CN,
--CO2H, --C(═O)NH2 or halogen (such as chloro, bromo or
fluoro).

[0042] In another aspect of the invention, R1 represents phenyl
optionally substituted by a group selected from --OCH3, --CN or
halogen (such as chloro, bromo or fluoro).

[0043] In another aspect of the invention, R1 represents phenyl
substituted by a group selected from --OCH3, --CN or halogen (such
as chloro, bromo or fluoro).

[0044] In another aspect of the invention, R1 represents phenyl
substituted by fluoro.

[0045] In another aspect of the invention, R1 represents phenyl.

[0046] In one aspect of the invention, R3 and R4 each
independently represent H. In another aspect of the invention, R3
and R4 each independently represent fluoro.

[0047] In another aspect of the invention, R3 and R4 each
independently represent --C1-4alkyl (such as --CH3). In another
aspect of the invention, R3 and R4 each independently represent
--CH3. In another aspect of the invention, R3 and R4 each
independently represent --OC1-4alkyl (such as --CH3). In
another aspect of the invention, R3 and R4 each independently
represent --OCH3.

[0048] In one aspect of the invention, R3 represents fluoro when
R4 represents H. In another aspect of the invention, R3
represents H when R4 represents fluoro.

[0049] In one aspect of the invention, R3 represents --OCH3 when
R4 represents H. In another aspect of the invention, R3
represents H when R4 represents --OCH3.

[0050] In one aspect of the invention, R3 represents --CH3 when
R4 represents H. In another aspect of the invention, R3
represents H when R4 represents --CH3.

[0051] In one aspect of the invention, R5 represents H,
--C1-4alkyl (such as --CH3 or --C2H5),
--OC1-4alkyl (such as --OCH3), --CO2C1-4alkyl (such
as --CO2O2H5), --CN, --C1-4alkylCN (such as
--CH2CN), --C1-4haloalkyl (such as --CF3),
--OC1-4haloalkyl (such as --OCF3), --C(═O)C1-4alkyl
(such as --C(═O)CH3), --XC(═O)C1-4alkyl (such as
--XC(═O)CH3) or halogen (such as chloro, bromo or fluoro).

[0052] In another aspect of the invention R5 represents
--C1-4alkyl (such as --CH3), --OC1-4alkyl (such as
--OCH3), --CO2C1-4alkyl (such as --CO2O2H5)
or halogen (such as chloro, bromo or fluoro).

[0054] In another aspect of the invention, R5 represents --CH3,
--OCH3, --CO2C2H5 or halogen (such as chloro, bromo
or fluoro).

[0055] In another aspect of the invention, R5 represents --OCH3.
In another aspect of the invention, R5 represents
--CO2C2H5. In another aspect of the invention, R5
represents halogen (such as chloro, bromo or fluoro). In another aspect
of the invention, R5 represents --CH3. In another aspect of the
invention, R5 represents --C2H5 (ethyl). In another aspect
of the invention, R5 represents --CN. In another aspect of the
invention, R5 represents --CH2CN. In another aspect of the
invention, R5 represents --CF3. In another aspect of the
invention, R5 represents --OCF3. In another aspect of the
invention, R5 represents H or bromo. In another aspect of the
invention, R5 represents H. In another aspect of the invention,
R5 represents halogen. In another aspect of the invention, R5
represents bromo. In another aspect of the invention, R5 represents
fluoro.

[0057] In another aspect of the invention, R5 represents
--C6-10aryl (such as phenyl), --C5-10heteroaryl or
--C5-10heterocyclyl wherein the --C6-10aryl,
--C5-10heteroaryl or --C5-10heterocyclyl is optionally
substituted by one, two or three groups independently selected from
--C1-4alkyl (such as --CH3), --OC1-4alkyl (such as
--OCH3), --C2-4alkenyl (such as --CH2CH═CHCH2),
--OH, --C1-4alkyleneOH (such as --CH2OH), --C1-4haloalkyl
(such as --CF3), --CN, --CO2H, --C1-4alkyleneCO2H
(such as --CH2CO2H), --XC(═O)C1-4alkyl (such as
--XC(═O)CH3), --Si(C1-3alkyl)3 (such as
--Si(CH3)3) or halogen (such as chloro, bromo or fluoro).

[0059] In another aspect of the invention, R5 represents
--C6-10aryl (such as phenyl), --C5-10heteroaryl or
--C5-10heterocyclyl wherein the --C6-10aryl,
--C5-10heteroaryl or --C5-10heterocyclyl is substituted by one,
two or three groups independently selected from --C1-4alkyl (such as
--CH3), --OC1-4alkyl (such as --OCH3), --C2-4alkenyl
(such as --CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such
as --CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3) or halogen
(such as chloro, bromo or fluoro).

[0061] In another aspect of the invention, R5 represents
--C6-10aryl (such as phenyl), --C5-10heteroaryl or
--C5-10heterocyclyl wherein the --C6-10aryl,
--C5-10heteroaryl or --C5-10heterocyclyl is substituted by one
or two groups independently selected from --C1-4alkyl (such as
--CH3), --OC1-4alkyl (such as --OCH3), --C2-4alkenyl
(such as --CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such
as --CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3) or halogen
(such as chloro, bromo or fluoro).

[0063] In another aspect of the invention, R5 represents
--C6-10aryl (such as phenyl), --C5-10heteroaryl or
--C5-10heterocyclyl wherein the --C6-10aryl,
--C5-10heteroaryl or --C5-10heterocyclyl is substituted by a
group independently selected from --C1-4alkyl (such as --CH3),
--OC1-4alkyl (such as --OCH3), --C2-4alkenyl (such as
--CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such as
--CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3) or halogen
(such as chloro, bromo or fluoro).

[0064] In another aspect of the invention R5 represents
--C6-10aryl (such as phenyl) optionally substituted by one, two or
three groups independently selected from --C1-4alkyl (such as
--CH3), --OC1-4alkyl (such as --OCH3), --C2-4alkenyl
(such as --CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such
as --CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3),
--SO2NR9R10, --C(═O)NR9R10,
--NR9R10 or halogen (such as chloro, bromo or fluoro).

[0065] In another aspect of the invention, R5 represents
--C6-10aryl (such as phenyl) optionally substituted by one, two or
three groups independently selected from --C1-4alkyl (such as
--CH3), --OC1-4alkyl (such as --OCH3), --C2-4alkenyl
(such as --CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such
as --CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3) or halogen
(such as chloro, bromo or fluoro).

[0066] In another aspect of the invention R5 represents
--C6-10aryl (such as phenyl) substituted by one, two or three groups
independently selected from --C1-4alkyl (such as --CH3),
--OC1-4alkyl (such as --OCH3), --C2-4alkenyl (such as
--CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such as
--CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3),
--SO2NR9R10, --C(═O)NR9R10,
--NR9R10 or halogen (such as chloro, bromo or fluoro).

[0067] In another aspect of the invention, R5 represents
--C6-10aryl (such as phenyl) substituted by one, two or three groups
independently selected from --C1-4alkyl (such as --CH3),
--OC1-4alkyl (such as --OCH3), --C2-4alkenyl (such as
--CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such as
--CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3) or halogen
(such as chloro, bromo or fluoro).

[0068] In another aspect of the invention R5 represents
--C6-10aryl (such as phenyl) substituted by one or two groups
independently selected from --C1-4alkyl (such as --CH3),
--OC1-4alkyl (such as --OCH3), --C2-4alkenyl (such as
--CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such as
--CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3),
--SO2NR9R10, --C(═O)NR9R10,
--NR9R10 or halogen (such as chloro, bromo or fluoro).

[0069] In another aspect of the invention, R5 represents
--C6-10aryl (such as phenyl) substituted by one or two groups
independently selected from --C1-4alkyl (such as --CH3),
--OC1-4alkyl (such as --OCH3), --C2-4alkenyl (such as
--CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such as
--CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3) or halogen
(such as chloro, bromo or fluoro).

[0070] In another aspect of the invention R5 represents
--C6-10aryl (such as phenyl) substituted by a group independently
selected from --C1-4alkyl (such as --CH3), --OC1-4alkyl
(such as --OCH3), --C2-4alkenyl (such as
--CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such as
--CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3),
--SO2NR9R10, --C(═O)NR9R10,
--NR9R10 or halogen (such as chloro, bromo or fluoro).

[0071] In another aspect of the invention, R5 represents
--C6-10aryl (such as phenyl) substituted by a group independently
selected from --C1-4alkyl (such as --CH3), --OC1-4alkyl
(such as --OCH3), --C2-4alkenyl (such as
--CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such as
--CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3) or halogen
(such as chloro, bromo or fluoro).

[0082] In another aspect of the invention, R5 represents
--C5-10heteroaryl substituted by one or two groups independently
selected from --C1-4alkyl (such as --CH3), --OC1-4alkyl
(such as --OCH3), --C2-4alkenyl (such as
--CH2CH═CHCH2), --OH, --C1-4alkyleneOH (such as
--CH2OH), --C1-4haloalkyl (such as --CF3), --CN,
--CO2H, --C1-4alkyleneCO2H (such as --CH2CO2H),
--XC(═O)C1-4alkyl (such as --XC(═O)CH3),
--Si(C1-3alkyl)3 (such as --Si(CH3)3) or halogen
(such as chloro, bromo or fluoro).

[0084] In another aspect of the invention, R5 represents
--C5-10heteroaryl substituted by a group independently selected from
--C1-4alkyl (such as --CH3), --OC1-4alkyl (such as
--OCH3), --C2-4alkenyl (such as --CH2CH═CHCH2),
--OH, --C1-4alkyleneOH (such as --CH2OH), --C1-4haloalkyl
(such as --CF3), --CN, --CO2H, --C1-4alkyleneCO2H
(such as --CH2CO2H), --XC(═O)C1-4alkyl (such as
--XC(═O)CH3)--Si(C1-3alkyl)3 (such as
--Si(CH3)3) or halogen (such as chloro, bromo or fluoro).

[0087] In another aspect of the invention, R5 represents
--C5-10heteroaryl substituted by one or two groups independently
selected from --CH3, --OCH3, --CH2CH═CHCH2, --OH,
--CH2OH, --CF3, --CN, --CO2H, --CH2CO2H,
--XC(═O)CH3, --Si(CH3)3 or halogen (such as chloro,
bromo or fluoro).

[0088] In another aspect of the invention, R5 represents
--C5-10heteroaryl.

[0089] In another aspect of the invention, R5 represents
--C5-10heterocyclyl.

[0090] In another aspect of the invention, R5 represents
--C3-8cycloalkyl (such as cyclohexyl).

[0091] In another aspect of the invention, R5 represents pyridinyl.
In another aspect of the invention, R5 represents thiophene. In
another aspect of the invention, R5 represents benzodioxolane. In
another aspect of the invention, R5 represents benzodioxane. In
another aspect of the invention, R5 represents oxazole. In another
aspect of the invention, R5 represents pyrrole. In another aspect of
the invention, R5 represents cyclohexane.

[0092] In one aspect of the invention, X represents O. In another aspect
of the invention, X represents NR8.

[0093] In one aspect of the invention, R6 represents H. In another
aspect of the invention, R6 represents --C1-4alkyl. In another
aspect of the invention, R6 represents --CH3. In another aspect
of the invention, R6 represents H or chloro. In another aspect of
the invention, R6 represents chloro. In another aspect of the
invention, R6 represents CN.

[0094] In one aspect of the invention, R7 represents H. In another
aspect of the invention, R7 represents --C1-4alkyl. In another
aspect of the invention, R7 represents --CH3.

[0095] In one aspect of the invention, R8 represents H. In another
aspect of the invention, R8 represents --C1-4alkyl. In another
aspect of the invention, R8 represents --CH3.

[0096] In one aspect of the invention, R9 represents H. In another
aspect of the invention, R9 represents --C1-4alkyl. In another
aspect of the invention, R9 represents --CH3.

[0097] In one aspect of the invention, R10 represents H. In another
aspect of the invention, represents --C1-4alkyl. In another aspect
of the invention, R10 represents --CH3.

[0098] Each of the aspects of the invention are independent unless stated
otherwise. Nevertheless the skilled person will understand that all the
permutations of the aspects herein described are within the scope of the
invention. Thus it is to be understood that the present invention covers
all combinations of suitable, convenient and exemplified aspects
described herein.

[0099] As used herein, the term "alkyl" refers to straight or branched
hydrocarbon chains containing the specified number of carbon atoms. For
example, --C1-4alkyl refers to a straight or branched "alkyl"
containing at least 1, and at most 4, carbon atoms. Examples of "alkyl"
as used herein include, but are not limited to, methyl, ethyl, n-propyl,
n-butyl, isobutyl, isopropyl and t-butyl.

[0100] As used herein, the term "alkylene" refers to straight or branched
chain saturated hydrocarbon linker groups containing the specified number
of carbon atoms. For example, --C1-4alkylene refers to a straight or
branched "alkylene" containing at least 1, and at most 4, carbon atoms.
Examples of "alkylene" as used herein include, but are not limited to,
methylene (--CH2--) and ethylene (--CH2CH2--).

[0101] As used herein, the term "alkenyl` refers to straight or branched
unsaturated hydrocarbon groups, wherein the unsaturation is present only
as double bonds and containing the specified number of carbon atoms. For
example --C2-4alkenyl refers to straight or branched chain
unsaturated hydrocarbon groups containing one or more double bond(s) and
having from 2 to 4 carbon atoms. Examples of "alkenyl" as used herein
include, but are not limited to, ethenyl (--CH═CH2) and propenyl
(--CH═CHCH3 or --CH2CH═CH2).

[0102] As used herein, the term "--C6-10aryl" refers to an aromatic
carbocyclic moiety containing 6 to 10 carbon ring-atoms. The definition
includes both monocyclic and bicyclic ring systems and bicyclic
structures at least a portion of which is aromatic and the other part is
saturated, partially or fully unsaturated. Examples of aryl groups as
used herein include, but are not limited to, naphthyl, anthryl,
phenanthryl, indanyl, indenyl, azulenyl, azulanyl, fluorenyl, phenyl and
naphthyl; and more specifically phenyl.

[0103] As used herein, the term "--C3-8cycloalkyl" as used herein
refers to a saturated monocyclic hydrocarbon ring of 3 to 8 carbon atoms.
Examples of such groups as used herein include, but are not limited to,
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or
cyclooctyl; and more specifically cyclohexyl.

[0104] As used herein, the term "halogen" or "halo" refers to a fluorine
(fluoro), chlorine (chloro), bromine (bromo) or iodine (iodo) atom.

[0105] As used herein, the term "haloalkyl" refers to an alkyl group
having one or more carbon atoms and wherein at least one hydrogen atom is
replaced with a halogen atom, for example a fluoro atom. For example,
--C1-4haloalkyl refers to an alkyl group containing at least 1, and
at most 4, carbon atoms and at least one halogen atom, for example a
fluoro atom. Examples of "haloalkyl" groups as used herein include, but
are not limited to, trifluoromethyl (--CF3).

[0106] As used herein, the term "-(5-10 membered heteroaryl)" or
"--C5-10heteroaryl" refers to an aromatic cyclic group containing 5
to 9 ring-atoms 1, 2, 3 or 4 of which are hetero-atoms independently
selected from nitrogen, oxygen and sulphur and the remaining ring-atoms
are carbon, e.g. benzothiophene. This definition includes both monocyclic
and bicyclic ring systems and bicyclic structures at least a portion of
which is aromatic and the other part is saturated, partially or fully
unsaturated.

[0107] As used herein, the term "-(5-10 membered heterocyclyl)" or
"--C5-10heterocyclyl" refers to a cyclic group containing 5 to 9
ring-atoms 1, 2, 3 or 4 of which are hetero-atoms independently selected
from nitrogen, oxygen and sulphur and the remaining ring-atoms are
carbon, wherein said cyclic group is saturated, partially or fully
unsaturated but, which is not aromatic. This definition includes bicyclic
structures provided the moiety is non-aromatic.

[0108] As used herein, the term "substituted" refers to substitution with
the named substituent or substituents, multiple degrees of substitution
being allowed unless otherwise stated.

[0109] For the avoidance of doubt, the term "independently" means that
where more than one substituent is selected from a number of possible
substituents, those substituents may be the same or different.

[0110] Also included in the present invention are pharmaceutically
acceptable salt complexes. In certain embodiments of the invention,
pharmaceutically acceptable salts of the compounds according to formula I
may be preferred over the respective free base or free acid because such
salts impart greater stability or solubility to the molecule thereby
facilitating formulation into a dosage form. Therefore, the present
invention also covers the pharmaceutically acceptable salts of the
compounds of formula (I).

[0111] Therefore, in one aspect of the invention there is provided a
compound of formula (I) or a salt thereof wherein the salt is a
pharmaceutically acceptable salt.

[0112] As used herein, the term "pharmaceutically acceptable", refers to
salts, molecular entities and other ingredients of compositions that are
generally physiologically tolerable and do not typically produce untoward
reactions when administered to a subject (e.g. human). The term
"pharmaceutically acceptable" also means approved by a regulatory agency
of the Federal or a state government or listed in the U.S. Pharmacopoeia
or other generally recognized pharmacopoeia for use in a subject, and
more particularly in humans.

[0113] As used herein, the term "subject" refers to an animal, in
particular a mammal and more particularly to a human or a domestic animal
or an animal serving as a model for a disease (e.g., mouse, monkey,
etc.). In one aspect, the subject is a human.

[0114] Salts of compounds of formula (I) which are suitable for use in
medicine are those wherein the counterion is pharmaceutically acceptable.
However, salts having non-pharmaceutically acceptable counterions are
within the scope of the present invention, for example, for use as
intermediates in the preparation of other compounds of formula (I) and
their pharmaceutically acceptable salts.

[0115] Suitable pharmaceutically acceptable salts will be apparent to
those skilled in the art and include for example base addition salts e.g.
ammonium salts, alkali metal salts such as those of sodium and potassium,
alkaline earth metal salts such as those of calcium and magnesium and
salts with organic bases, including salts of primary, secondary and
tertiary amines, such as isopropylamine, diethylamine, ethanolamine,
trimethylamine, dicyclohexyl amine and N-methyl-D-glucamine or for
example acid addition salts formed from acids which form non-toxic salts
e.g. hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate,
nitrate, phosphate, hydrogen phosphate, acetate, maleate, malate,
fumarate, lactate, tartrate, citrate, formate, gluconate, succinate,
piruvate, oxalate, oxaloacetate, trifluoroacetate, saccharate, benzoate,
methansulphonate, ethanesulphonate, benzenesulphonate,
p-toluensulphonate, methanesulphonic, ethanesulphonic,
p-toluenesulphonic, and isethionate. For a review on suitable salts see
Berge et al. J. Pharm. Sci., 1977, 66, 1-19. The invention includes
within its scope all possible stoichiometric and non-stoichiometric forms
of the salts of the compounds of formula (I).

[0116] Those skilled in the art of organic chemistry will appreciate that
many organic compounds can form complexes with solvents in which they are
reacted or from which they are precipitated or crystallized. These
complexes are known as "solvates".

[0117] Solvates of the compounds of formula (I) and solvates of the salts
of the compounds of formula (I) are included within the scope of the
present invention.

[0118] As used herein, the term "solvate" refers to a complex of variable
stoichiometry formed by a solute (in this invention, a compound of
formula (I) or a salt thereof) and a solvent. Such solvents for the
purpose of the invention may not interfere with the biological activity
of the solute. Examples of suitable solvents include, but are not limited
to, water, methanol, ethanol and acetic acid. Preferably the solvent used
is a pharmaceutically acceptable solvent. Most preferably the solvent
used is water and the solvate may also be referred to as a hydrate.

[0119] Solvates of compounds of formula (I) which are suitable for use in
medicine are those wherein the solvent is pharmaceutically acceptable.
However, solvates having non-pharmaceutically acceptable solvents are
within the scope of the present invention, for example, for use as
intermediates in the preparation of other compounds of formula (I) and
their pharmaceutically acceptable salts.

[0120] In one aspect, the compounds of formula (I) may be in the form of
pharmaceutically acceptable salts, solvates or solvates of salts. In a
further aspect, the compounds of formula (I) may be in the form of
pharmaceutically acceptable salts.

[0121] As used herein, the term "compounds of the invention" means the
compounds according to formula (I) and pharmaceutically acceptable salts
thereof. The term "a compound of the invention" means any one of the
compounds of the invention as defined below.

[0122] Prodrugs of the compounds of formula (I) are included within the
scope of the present invention.

[0123] As used herein, the term "prodrug" means a compound which is
converted within the body, e.g. by hydrolysis in the blood, into its
active form that has medical effects. Pharmaceutically acceptable
prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel
Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward
B. Roche, ed., Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Pergamon Press, 1987 and in D. Fleishner,
S. Ramon and H. Barba "Improved oral drug delivery: solubility
limitations overcome by the use of prodrugs", Advanced Drug Delivery
Reviews (1996) 19(2) 115-130. Prodrugs are any covalently bonded carriers
that release a compound of structure (I) in vivo when such prodrug is
administered to a patient. Prodrugs are generally prepared by modifying
functional groups in a way such that the modification is cleaved in vivo
yielding the parent compound. Prodrugs may include, for example,
compounds of this invention wherein hydroxy or amine groups are bonded to
any group that, when administered to a patient, cleaves to form the
hydroxy or amine groups. Thus, representative examples of prodrugs
include (but are not limited to) phosphonate, carbamate, acetate, formate
and benzoate derivatives of hydroxy and amine functional groups of the
compounds of formula (I).

[0124] Certain compounds of formula (I) may exist in stereoisomeric forms
(e.g. they may contain one or more asymmetric carbon atoms). The
individual stereoisomers (enantiomers and diastereomers) and mixtures or
racemic mixtures thereof are included within the scope of the present
invention.

[0125] Likewise, it is understood that compounds of formula (I) may exist
in tautomeric forms other than that shown in the formula and these are
also included within the scope of the present invention. In particular,
compounds of formula (I) may exist in the following tautomeric forms when
R7 is H.

##STR00004##

[0126] All possible tautomeric forms of the compounds of formula (I) are
contemplated to be within the scope of the present invention.

[0127] It will be appreciated that racemic compounds of formula (I) may be
optionally resolved into their individual enantiomers. Such resolutions
may conveniently be accomplished by standard methods known in the art.
For example, a racemic compound of formula (I) may be resolved by chiral
preparative HPLC. An individual stereoisomer may also be prepared from a
corresponding optically pure intermediate or by resolution, such as
H.P.L.C. of the corresponding mixture using a suitable chiral support or
by fractional crystallisation of the diastereoisomeric salts formed by
reaction of the corresponding mixture with a suitable optically active
acid or base, as appropriate.

[0128] It will be appreciated that compounds of the invention may exist as
geometric isomers (cis/trans or (E)/(Z)). The present invention includes
the individual geometric isomers of the compounds of the invention and,
where appropriate, mixtures thereof. The compounds of formula (I) may be
in crystalline or amorphous form. Furthermore, some of the crystalline
forms of the compounds of formula (I) may exist as polymorphs, which are
included in the present invention.

[0376] Compounds of the invention have been found to activate AMPK and may
therefore be useful in the treatment of diabetes, metabolic syndrome,
atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia,
cognitive defect and cancer.

[0377] Within the context of the present invention, the terms describing
the indications used herein are classified in the Merck Manual of
Diagnosis and Therapy, 17th Edition and/or the International
Classification of Diseases 10th Edition (ICD-10). The various
subtypes of the disorders mentioned herein are contemplated as part of
the present invention.

[0378] In one aspect, the invention provides a compound of formula (I) or
a pharmaceutically acceptable salt thereof for use in medical therapy.

[0379] In one aspect, the invention provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for treating a disease or a condition
mediated by AMPK activation.

[0381] In another aspect, the invention provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for treating diabetes, metabolic syndrome,
atherosclerosis, dyslipidaemia, obesity, hypertension, cerebral ischemia,
cognitive defect and cancer.

[0382] In another aspect, the invention provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for treating type 2 diabetes, obesity or
dyslipidaemia.

[0383] In another aspect, the invention provides the use of a compound of
formula (I) or a pharmaceutically acceptable salt thereof for the
manufacture of a medicament for treating type 2 diabetes, dyslipidaemia
and cancer.

[0384] In one aspect, the invention provides a compound of formula (I) or
a pharmaceutically acceptable salt thereof for use in treating a disease
or a condition mediated by AMPK activation.

[0386] In another aspect, the invention provides a compound of formula (I)
or a pharmaceutically acceptable salt thereof for use in treating
diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity,
hypertension, cerebral ischemia, cognitive defect and cancer.

[0387] In another aspect, the invention provides a compound of formula (I)
or a pharmaceutically acceptable salt thereof for use in treating type 2
diabetes, obesity or dyslipidaemia.

[0388] In another aspect, the invention provides a compound of formula (I)
or a pharmaceutically acceptable salt thereof for use in treating type 2
diabetes, dyslipidaemia and cancer.

[0389] In one aspect, the invention provides a method of treating a
disease or a condition mediated by AMPK activation, which method
comprises administering to a subject, for example a mammal, including
human, a therapeutically effective amount of a compound of formula (I) or
a pharmaceutically acceptable salt thereof.

[0391] In another aspect, the invention provides a method of treating
diabetes, metabolic syndrome, atherosclerosis, dyslipidaemia, obesity,
hypertension, cerebral ischemia, cognitive defect and cancer, which
method comprises administering to a subject, for example a mammal,
including human, a therapeutically effective amount of a compound of
formula (I) or a pharmaceutically acceptable salt thereof.

[0392] In another aspect, the invention provides a method of treating type
2 diabetes, obesity or dyslipidaemia, which method comprises
administering to a subject, for example a mammal, including human, a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.

[0393] In another aspect, the invention provides a method of treating type
2 diabetes, dyslipidaemia and cancer, which method comprises
administering to a subject, for example a mammal, including human, a
therapeutically effective amount of a compound of formula (I) or a
pharmaceutically acceptable salt thereof.

[0394] It will be appreciated that reference to "treatment" and "therapy"
includes acute treatment or prophylaxis as well as the alleviation of
established symptoms and/or retardation of progression of the disease,
and may include the suppression of symptom recurrence in an asymptomatic
patient.

[0395] It will be appreciated that reference to "treatment" and "therapy"
includes acute treatment as well as the alleviation of established
symptoms and/or retardation of progression of the disease, and may
include the suppression of symptom recurrence in an asymptomatic patient.

Pharmaceutical Compositions

[0396] While it is possible that, for use in the methods of the invention,
a compound of formula (I) or a pharmaceutically acceptable salt thereof
may be administered as the bulk substance, it is preferable to present
the active ingredient in a pharmaceutical formulation, for example,
wherein the agent is in admixture with at least one pharmaceutically
acceptable carrier selected with regard to the intended route of
administration and standard pharmaceutical practice.

[0397] Accordingly, the present invention also includes a pharmaceutical
composition comprising a) a compound of formula (I) or a pharmaceutically
acceptable salt thereof and b) one or more pharmaceutically acceptable
carriers.

[0398] The term "pharmaceutically acceptable carrier" refers to a diluent,
excipient, and/or vehicle with which an active compound is administered.
The pharmaceutical compositions of the invention may contain combinations
of more than one carrier. Such pharmaceutical carriers can be sterile
liquids, such as water, saline solutions, aqueous dextrose solutions,
aqueous glycerol solutions, and oils, including those of petroleum,
animal, vegetable or synthetic origin, such as peanut oil, soybean oil,
mineral oil, sesame oil and the like. Water or aqueous solution saline
solutions and aqueous dextrose and glycerol solutions are preferably
employed as carriers, particularly for injectable solutions. Suitable
pharmaceutical carriers or diluents are well known in the pharmaceutical
art, and are described, for example, in "Remington's Pharmaceutical
Sciences" by E. W. Martin, 18th Edition. The choice of pharmaceutical
carrier can be selected with regard to the intended route of
administration and standard pharmaceutical practice. The pharmaceutical
compositions may comprise as, in addition to, the carrier any suitable
binder(s), lubricant(s), suspending agent(s) and/or coating agent(s).

[0399] The carrier, diluent and/or excipient must be "pharmaceutically
acceptable" in the sense of being compatible with the other ingredients
of the composition and not deleterious to the recipient thereof.

[0400] An "pharmaceutically acceptable excipient" means an excipient that
is useful in preparing a pharmaceutical composition that is generally
safe, non-toxic and neither biologically nor otherwise undesirable, and
includes an excipient that is acceptable for veterinary use as well as
human pharmaceutical use.

[0401] Examples of pharmaceutically acceptable diluent(s) useful in the
compositions of the invention include, but are not limited to water,
ethanol, propylene glycol and glycerine.

[0406] Preservatives, stabilisers, dyes and even flavouring agents may be
provided in the pharmaceutical composition. Examples of preservatives
include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
Antioxidants and suspending agents may be also used.

[0407] The present invention relates to a pharmaceutical composition for
the treatment of type 2 diabetes, dyslipidaemia or cancer comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0408] The present invention relates to a pharmaceutical composition for
the treatment of type 2 diabetes, obesity or dyslipidaemia comprising a
compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0409] The present invention further relates to a pharmaceutical
composition comprising a) 10 to 2000 mg of a compound of formula (I) or a
pharmaceutically acceptable salt thereof, and b) 0.1 to 2 g of one or
more pharmaceutically acceptable carriers.

[0410] The compounds of the invention may be administered in conventional
dosage forms prepared by combining a compound of the invention with
standard pharmaceutical carriers or diluents according to conventional
procedures well known in the art. These procedures may involve mixing,
granulating and compressing or dissolving the ingredients as appropriate
to the desired preparation.

[0411] The pharmaceutical compositions of the invention may be formulated
for administration by any suitable route, and include those in a form
adapted for oral, parenteral, transdermal, inhalation, sublingual,
topical, implant, nasal, enterally (or other mucosally) administration to
mammals including humans. The pharmaceutical compositions may be
formulated in conventional manner using one or more pharmaceutically
acceptable carriers or excipients. In one aspect, the pharmaceutical
composition is formulated for oral administration

[0412] The compositions may be in the form of tablets, capsules, powders,
granules, lozenges, such as oral or sterile parenteral solutions or
suspensions.

[0413] Tablets and capsules for oral administration may be in unit dose
presentation form, and may contain conventional excipients such as
binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth,
or polyvinylpyrrolidone; fillers, for example lactose, sugar,
maize-starch, calcium phosphate, sorbitol or glycine; tabletting
lubricants, for example magnesium stearate, talc, polyethylene glycol or
silica; disintegrants, for example potato starch; or acceptable wetting
agents such as sodium lauryl sulphate. The tablets may be coated
according to methods well known in normal pharmaceutical practice.

[0414] Oral liquid preparations may be in the form of, for example,
aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or
may be presented as a dry product for reconstitution with water or other
suitable vehicle before use. Such liquid preparations may contain
conventional additives, such as suspending agents, for example sorbitol,
methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,
carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible
fats, emulsifying agents, for example lecithin, sorbitan monooleate, or
acacia; non-aqueous vehicles (which may include edible oils), for example
almond oil, oily esters such as glycerine, propylene glycol, or ethyl
alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or
sorbic acid, and, if desired, conventional flavouring or colouring
agents.

[0415] For parenteral administration, fluid unit dosage forms are prepared
utilising the compound and a sterile vehicle, water being preferred. The
compound, depending on the vehicle and concentration used, can be either
suspended or dissolved in the vehicle. In preparing solutions the
compound can be dissolved in water for injection and filter sterilised
before filling into a suitable vial or ampoule and sealing.

[0416] The compounds of the invention may also, for example, be formulated
as suppositories containing conventional suppository bases e.g. cocoa
butter or other glyceride for use in human or veterinary medicine or as
pessaries e.g., containing conventional pessary bases.

[0417] The topical formulations of the present invention may be presented
as, for instance, ointments, creams or lotions, eye ointments and eye or
ear drops, impregnated dressings and aerosols, and may contain
appropriate conventional additives such as preservatives, solvents to
assist drug penetration and emollients in ointments and creams.

[0418] As indicated, the compound of the present invention can be
administered intranasally or by inhalation and is conveniently delivered
in the form of a dry powder inhaler or an aerosol spray presentation from
a pressurized container, pump, spray or nebulizer with the use of a
suitable propellant, e.g., a hydrofluoroalkane such as
1,1,1,2-tetrafluoroethane (HFA 134AT) or 1,1,1,2,3,3,3-heptafluoropropane
(HFA 227EA), or a mixture thereof. In the case of a pressurized aerosol,
the dosage unit may be determined by providing a valve to deliver a
metered amount. The pressurized container, pump, spray or nebulizer may
contain a solution or suspension of the active compound, e.g., using a
mixture of ethanol and the propellant as the solvent, which may
additionally contain a lubricant e.g. sorbitan trioleate.

[0419] Capsules and cartridges (made, for example, from gelatin) for use
in an inhaler or insufflator may be formulated to contain a powder mix of
the compound and a suitable powder base such as lactose or starch.

[0420] Advantageously, agents such as a local anaesthetic, preservative
and buffering agent can be dissolved in the vehicle. To enhance the
stability, the composition can be frozen after filling into the vial and
the water removed under vacuum. The dry lyophilised powder is then sealed
in the vial and an accompanying vial of water for injection may be
supplied to reconstitute the liquid prior to use. Parenteral suspensions
are prepared in substantially the same manner except that the compound is
suspended in the vehicle instead of being dissolved and sterilisation
cannot be accomplished by filtration. The compound can be sterilised by
exposure to ethylene oxide before suspending in the sterile vehicle.
Advantageously, a surfactant or wetting agent is included in the
composition to facilitate uniform distribution of the compound.

[0421] The compounds of the invention may be administered for immediate-,
delayed-, modified-, sustained-, pulsed- or controlled-release
applications.

[0422] In one aspect, oral compositions are slow, delayed or positioned
release (e.g., enteric especially colonic release) tablets or capsules.
This release profile can be achieved, for example, by use of a coating
resistant to conditions within the stomach but releasing the contents in
the colon or other portion of the GI tract wherein a lesion or
inflammation site has been identified. Or a delayed release can be
achieved by a coating that is simply slow to disintegrate. Or the two
(delayed and positioned release) profiles can be combined in a single
formulation by choice of one or more appropriate coatings and other
excipients. Such formulations constitute a further feature of the present
invention.

[0423] Suitable compositions for delayed or positioned release and/or
enteric coated oral formulations include tablet formulations film coated
with materials that are water resistant, pH sensitive, digested or
emulsified by intestinal juices or sloughed off at a slow but regular
rate when moistened. Suitable coating materials include, but are not
limited to, hydroxypropyl methylcellulose, ethyl cellulose, cellulose
acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl
methylcellulose phthalate, polymers of metacrylic acid and its esters,
and combinations thereof. Plasticizers such as, but not limited to
polyethylene glycol, dibutylphthalate, triacetin and castor oil may be
used. A pigment may also be used to color the film. Suppositories are be
prepared by using carriers like cocoa butter, suppository bases such as
Suppocire C, and Suppocire NA50 (supplied by Gattefosse Deutschland GmbH,
D-Weil am Rhein, Germany) and other Suppocire type excipients obtained by
interesterification of hydrogenated palm oil and palm kernel oil
(C8-C18 triglycerides), esterification of glycerol and specific
fatty acids, or polyglycosylated glycerides, and whitepsol (hydrogenated
plant oils derivatives with additives). Enemas are formulated by using
the appropriate active compound according to the present invention and
solvents or excipients for suspensions. Suspensions are produced by using
micronized compounds, and appropriate vehicle containing suspension
stabilizing agents, thickeners and emulsifiers like
carboxymethylcellulose and salts thereof, polyacrylic acid and salts
thereof, carboxyvinyl polymers and salts thereof, alginic acid and salts
thereof, propylene glycol alginate, chitosan, hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose,
methylcellulose, polyvinyl alcohol, polyvinyl pyrrolidone,
N-vinylacetamide polymer, polyvinyl methacrylate, polyethylene glycol,
pluronic, gelatin, methyl vinyl ether-maleic anhydride copolymer, soluble
starch, pullulan and a copolymer of methyl acrylate and 2-ethylhexyl
acrylate lecithin, lecithin derivatives, propylene glycol fatty acid
esters, glycerin fatty acid esters, sorbitan fatty acid esters,
polyoxyethylene sorbitan fatty acid esters, polyethylene glycol fatty
acid esters, polyoxyethylene hydrated caster oil, polyoxyethylene alkyl
ethers, and pluronic and appropriate buffer system in pH range of 6.5 to
8. The use of preservatives, masking agents is suitable. The average
diameter of micronized particles can be between 1 and 20 micrometers, or
can be less than 1 micrometer. Compounds can also be incorporated in the
formulation by using their water-soluble salt forms.

[0424] Alternatively, materials may be incorporated into the matrix of the
tablet e.g. hydroxypropyl methylcellulose, ethyl cellulose or polymers of
acrylic and metacrylic acid esters. These latter materials may also be
applied to tablets by compression coating.

[0425] The compositions may contain from 0.1% by weight, preferably from
10-60% by weight, of the active ingredient, depending on the method of
administration. Where the compositions comprise dosage units, each unit
will preferably contain from 50-500 mg of the active ingredient. The
dosage as employed for adult human treatment will preferably range from
100 to 3000 mg per day, for instance 1500 mg per day depending on the
route and frequency of administration. Such a dosage corresponds to 1.5
to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg/kg per day.

[0426] Since the compounds of the invention are intended for use in
pharmaceutical compositions it will readily be understood that they are
each preferably provided in substantially pure form, for example at least
60% pure, more suitably at least 75% pure and preferably at least 85%,
especially at least 98% pure (% are on a weight for weight basis). Impure
preparations of the compounds may be used for preparing the more pure
forms used in the pharmaceutical compositions; these less pure
preparations of the compounds should contain at least 1%, more suitably
at least 5% and preferably from 10 to 59% of a compound of the invention.

[0427] It will be recognised by one of skill in the art that the optimal
quantity and spacing of individual dosages of a compound of the invention
will be determined by the nature and extent of the condition being
treated, the form, route and site of administration, and the particular
mammal being treated, and that such optimums can be determined by
conventional techniques. It will also be appreciated by one of skill in
the art that the optimal course of treatment, i.e., the number of doses
of a compound of the invention given per day for a defined number of
days, can be ascertained by those skilled in the art using conventional
course of treatment determination tests.

[0428] The compounds of formula (I) or pharmaceutically acceptable salt(s)
thereof may also be used in combination with other therapeutic agents.
The invention thus provides, in a further aspect, a combination
comprising a) a compound of formula (I) or pharmaceutically acceptable
salt thereof and b) one or more further therapeutically active agent(s).

[0429] The combinations referred to above may conveniently be presented
for use in the form of a pharmaceutical composition and thus
pharmaceutical compositions comprising a combination as defined above
together with one or more pharmaceutically acceptable carriers thereof
represent a further aspect of the invention.

[0430] Compounds of the invention may be administered in combination with
other therapeutically active agents. Preferred therapeutic agents are
selected from the list consisting of: insulin, bisguanidine, metformin, a
DPP-IV inhibitor, sitagliptin, an inhibitor of cholesteryl ester
transferase (CETP inhibitors), a HMG-CoA reductase inhibitor, a
microsomal triglyceride transfer protein, a peroxisome
proliferator-activated receptor activator (PPAR), a bile acid reuptake
inhibitor, a cholesterol absorption inhibitor, a cholesterol synthesis
inhibitor, a fibrate, niacin, an ion-exchange resin, an antioxidant, an
inhibitor of AcylCoA: cholesterol acyltransferase (ACAT inhibitor), a
cannabinoid 1 antagonist, a bile acid sequestrant, a corticosteroid, a
vitamin D3 derivative, a retinoid, an immunomodulator, an anti androgen,
a keratolytic agent, an anti-microbial, a platinum chemotherapeutic, an
antimetabolite, hydroxyurea, a taxane, a mitotic disrupter, an
anthracycline, dactinomycin, an alkylating agent and a cholinesterase
inhibitor.

[0431] When the compound of formula (I) or pharmaceutically acceptable
salt thereof is used in combination with a second therapeutically active
agent the dose of each compound may differ from that when the compound is
used alone. Appropriate doses will be readily appreciated by those
skilled in the art. It will be appreciated that the amount of a compound
of the invention required for use in treatment will vary with the nature
of the condition being treated and the age and the condition of the
patient and will be ultimately at the discretion of the attendant
physician or veterinarian.

[0432] The combinations referred to above may conveniently be presented
for use in the form of a pharmaceutical formulation and thus
pharmaceutical formulations comprising a combination as defined above
together with at least one pharmaceutically acceptable carrier and/or
excipient comprise a further aspect of the invention.

[0433] The individual components of such combinations may be administered
either sequentially or simultaneously in separate or combined
pharmaceutical formulations by any convenient route.

[0434] When administration is sequential, either the AMPK activator or the
second therapeutically active agent may be administered first. When
administration is simultaneous, the combination may be administered
either in the same or different pharmaceutical composition.

[0435] When combined in the same formulation it will be appreciated that
the two compounds must be stable and compatible with each other and the
other components of the formulation. When formulated separately they may
be provided in any convenient formulation, conveniently in such manner as
are known for such compounds in the art.

Methods of Preparation

[0436] Compounds of formula (I) and salts thereof may be prepared by the
general methods outlined hereinafter or any method known in the art, said
methods constituting a further aspect of the invention. R1 to
R7 are as defined above unless otherwise specified. Throughout the
specification, general formulae are designated by Roman numerals (I),
(II), (III), (IV) etc.

[0437] In a general process, compounds of formula (I), wherein R5 is
as defined above other than H or bromo (formula (Ia)), may be prepared
according to reaction scheme 1 by reacting compounds of formula (I),
wherein R5 is bromo (formula (Ib)), with the appropriate boronic
acid (IIa) in the presence of an inorganic base such as cesium carbonate
and a catalyst (such as Pd(PPh3)4) in a suitable solvent such
as a 1,4-dioxane/water mixture (suitably at 100 to 160° C.).

##STR00005##

[0438] Compounds of formula (IIa) are commercially available or may be
prepared by methods known in the literature or processes known to those
skilled in the art.

[0439] Compounds of formula (Ib) may be prepared according to Scheme 12.

[0440] Compounds of formula (I), wherein R5 is as defined above other
than H or bromo (formula (Ia)), may be alternatively prepared according
to reaction scheme 2 by reacting compounds of formula (Ic), with the
appropriate R5-halide (III) in the presence of an inorganic base
such as cesium carbonate and a catalyst (such as Pd(PPh3)4) in
a suitable solvent such as as a 1,4-dioxane/water mixture or a
1,4-dioxane/ethanol/water mixture (suitably at 100 to 160° C.).

##STR00006##

[0441] Compounds of formula (Ic) may be prepared according to Scheme 25.

[0442] Compounds of formula (III) are commercially available or may be
prepared by methods known in the literature or processes known to those
skilled in the art.

[0443] Compounds of formula (I), wherein R5 is as defined above other
than H or bromo (formula (Ia)), may be alternatively prepared according
to reaction scheme 3 by reacting compounds of formula (IVb), with the
appropriate R5-halide (III) in the presence of an inorganic base
such as cesium carbonate and a catalyst (such as Pd(PPh3)4) in
a suitable solvent such as a 1,4-dioxane/water mixture or a
1,4-dioxane/ethanol/water mixture (suitably at 100 to 160° C.).

##STR00007##

[0444] Compounds of formula (IVb) may be prepared according to Scheme 25.
Compounds of formula (I), wherein

##STR00008##

represents a --C6-10aryl, --C5-10heteroaryl,
--C5-10heterocyclyl or a --C5-10cycloalkyl group (formula
(Id)), may be alternatively prepared according to reaction scheme 4 by
reacting compounds of formula (Ie) in the presence of BBr3 in a
suitable solvent such as DCM (suitably at RT).

[0446] Compounds of formula (I), wherein R1 is phenyl substituted by
a carboxylic acid (formula (Ig)) or a carboxamide (formula (If)), may be
prepared according to reaction scheme 5 by reacting compounds of formula
(Ih) in the presence of KOH in a suitable solvent such as an
ethanol/water mixture.

[0448] Compounds of formula (I), wherein R5 is H (formula (Ii)), may
be prepared according to reaction scheme 6 by hydrogenating compounds of
formula (Ib) in the presence of a catalyst (such as Pd/C) in a suitable
solvent such as methanol.

##STR00011##

[0449] Compounds of formula (I), wherein R7 is --C1-4alkyl
(formula (Ij)) may be prepared according to reaction scheme 7 by reacting
compounds of formula (Ia) with a base such as sodium hydride in the
presence of a --C1-4alkylating agent (R7--X), such as methyl
iodide, in a suitable solvent such as DMF (suitably at 110° C.
under microwave irradiation).

##STR00012##

[0450] Compounds of formula R7--X are commercially available or may
be prepared by methods known in the literature or processes known to
those skilled in the art.

[0451] Compounds of formula (I), wherein R5 is --NHCOCH3
(formula (Ik)) may be prepared according to reaction scheme 8 by reacting
compounds of (I), wherein R5 is --NH2 (formula (Im)) with
acetyl chloride in a suitable solvent such as a THF/DMF mixture.
Compounds of formula (Im) may be prepared by reacting compounds of
formula (Ib) with ammonium hydroxide in the presence of a catalyst such
as copper iodide and a ligand such as 2,4-pentanedione in a suitable
solvent such as DMF (suitably at 100° C.).

##STR00013##

[0452] Compounds of formula (I), wherein R1 is H (formula (In)), may
be prepared according to reaction scheme 9 by reacting compounds of
formula (I), wherein R1 is --CO2C2H5 and R5 is
bromo (formula (Io)), with the appropriate R5-boron derivative (IIb)
such as the appropriate boronic acid in the presence of an inorganic base
such as cesium carbonate and a catalyst (such as Pd(PPh3)4) in
a suitable solvent such as 1,4-dioxane (suitably at 100 to 160°
C.).

##STR00014##

[0453] Compounds of formula (Io) may be prepared according to Scheme 12.

[0454] Compounds of formula (IIb) are commercially available or may be
prepared by methods known in the literature or processes known to those
skilled in the art.

[0455] Compounds of formula (I), wherein R1 is H and R5 is bromo
(formula (Ip)), may be prepared according to reaction scheme 10 by
reacting compounds of formula (I), wherein R1 is
--CO2C2H5 and R5 is bromo (formula (Io)), with KOH in
a suitable solvent such as water (suitably at 120° C.).

##STR00015##

[0456] Compounds of formula (I), wherein R5 is

##STR00016##

may be prepared according to reaction scheme 11 by reacting compounds of
formula (I), wherein R5 is bromo (formula (Ib)), with the
appropriate boronic acid (IIc) in the presence of an inorganic base such
as cesium carbonate and a catalyst (such as Pd(PPh3)4) in a
suitable solvent such as a 1,4-dioxane/water mixture (suitably at 100 to
160° C.).

##STR00017##

[0457] Compounds of formula (IIc) are commercially available or may be
prepared by methods known in the literature or processes known to those
skilled in the art.

[0458] Compounds of formula (I) may be prepared according to reaction
scheme 12 by reacting compounds of formula (IV) in the presence of a base
such as sodium hydride or potassium tertbutoxide or potassium
hexamethyldisilazane in a suitable solvent such as THF or DMSO (suitably
at room temperature or reflux).

[0460] Compounds of formula (IV) may be prepared according to reaction
scheme 13 by reacting compounds of formula (IV), wherein R5 is bromo
(formula (IVa)), with the appropriate R5-boron derivative (IIb) such
as an appropriate boronic acid or potassium trifluoroborate derivative in
the presence of an inorganic base such as cesium carbonate and a catalyst
(such as Pd(PPh3)4) in a suitable solvent such as 1,4-dioxane
(suitably at 100 to 160° C.).

##STR00019##

[0461] Compounds of formula (IVa) may be prepared according to Scheme 15.

[0462] Compounds of formula (IV) may be also prepared according to
reaction scheme 14 by reacting compounds of formula (IVb), with the
appropriate R5-halide derivative (III) in the presence of an
inorganic base such as cesium carbonate and a catalyst (such as
Pd(PPh3)4) in a suitable solvent such as 1,4-dioxane (suitably
at 100 to 160° C.).

##STR00020##

[0463] Compounds of formula (IVb) may be prepared according to Scheme 25.

[0464] Compounds of formula (IV) may also be prepared according to
reaction scheme 15 by reacting compounds of formula (V) with acetic acid
derivatives (VI) in the presence of a coupling reagent such as DCC or
EDC/HOBT or COMU and a base such as triethylamine in a suitable solvent
such as acetonitrile (suitably at room temperature) or with acetyl
chloride derivatives (VII) in the presence of a base such as
triethylamine in a suitable solvent such as DCM (suitably at room
temperature).

[0466] Compounds of formula (VI) or (VII) are commercially available or
may be prepared by methods known in the literature or processes known to
those skilled in the art.

[0467] Compounds of formula (V), wherein R6 is methyl (formula (Va)
may be prepared according to reaction scheme 16 by reacting compounds of
formula (V), wherein R6 is chlorine (formula (Vb)), in the presence
of trimethylboroxin, an inorganic base such as cesium carbonate and a
catalyst (such as palladium acetate and
{2',6'-bis[(1-methylethyl)oxy]-2-biphenylyl}(dicyclohexyl)phosphane as a
ligand) in a suitable solvent such as ethanol.

[0469] Compounds of formula (IV), wherein R6 is cyano (formula (IVc)
may be prepared according to reaction scheme 17 by reacting compounds of
formula (IV), wherein R6 is chlorine (formula (IVd)), in the
presence of zinc cyanide and a catalyst (such as palladium
trifluoroacetate and 2-(di-t-butylphosphino)-1,1'-binapthyl as a ligand)
in a suitable solvent such as N,N-dimethylacetamide.

##STR00023##

[0470] Compounds of formula (IVd) may be prepared according to Scheme 15.

[0471] Compounds of formula (V) may be prepared according to reaction
scheme 18 by reacting compounds of formula (V), wherein R5 is bromo
(formula (Vc)), with the appropriate R5-boron derivative (IIb) such
as the appropriate boronic acid or potassium trifluoroborate derivative
in the presence of an inorganic base such as cesium carbonate and a
catalyst (such as Pd(PPh3)4) in a suitable solvent such as
1,4-dioxane (suitably at 100 to 160° C.).

##STR00024##

[0472] Compounds of formula (Vc) may be prepared according to Scheme to
16, Scheme 19 and/or Scheme 20.

[0473] Compounds of formula (V) may be prepared according to reaction
scheme 19 by reacting compounds of formula (Vd), with the appropriate
R5-halide derivative (III) in the presence of an inorganic base such
as cesium carbonate and a catalyst (such as Pd(PPh3)4) in a
suitable solvent such as 1,4-dioxane (suitably at 100 to 160° C.).

##STR00025##

[0474] Compounds of formula (Vd) may be prepared according to Scheme 25.

[0475] Compounds of formula (V) may be prepared according to reaction
scheme 20 by reacting compounds of formula (VIII) in the presence of an
acid such as HCl in a suitable solvent such as ethanol (suitably at
reflux).

##STR00026##

[0476] Compounds of formula (VIII) may be prepared according to Scheme 21
and/or Scheme 22.

[0477] Compounds of formula (VIII), wherein R6 is chlorine (formula
(VIIIa)), may be prepared according to reaction scheme 21 by reacting
compounds of formula (IX), wherein R6 is H, with N-Chlorosuccinimide
(NCS) (commercially available) in a suitable solvent such as chloroform
(suitably at room temperature).

##STR00027##

[0478] Compounds of formula (IX) may be prepared according to Scheme 22.

[0479] Compounds of formula (VIII) may be alternatively prepared according
to reaction scheme 22 by reacting compounds of formula (X) with the
appropriate phenylboronic acid derivative (XI) or halide derivative (XII)
in the presence of a copper catalyst such as copper acetate or copper
iodide and a base such as pyridine or tripotassium phosphate and
N,N'-dimethyl-1,2-ethanediamine in a suitable solvent such as DCM
(suitably at room temperature) or toluene (suitably at reflux).

##STR00028##

[0480] Compounds of formula (X) may be prepared according to Scheme 23
and/or Scheme 24.

[0481] Compounds of formula (XI) and (XII) are commercially available or
may be prepared by methods known in the literature or processes known to
those skilled in the art.

[0482] Compounds of formula (X), wherein R6 is Cl (formula (Xa)), may
be prepared according to reaction scheme 23 by reacting compounds of
formula (Xb) with N-Chlorosuccinimide (NCS) (commercially available) in a
suitable solvent such as chloroform (suitably at room temperature).

##STR00029##

[0483] Compounds of formula (Xb) may be made according to Scheme 24.

[0484] Compounds of formula (X), wherein R6 is H (formula (Xb)), may
be prepared according to reaction scheme 24 by reacting a compound of
formula (XIV) with an acylchloride derivative of formula (VII) in the
presence of a base such as triethylamine in a suitable solvent such as
DCM (suitably at room temperature).

##STR00030##

[0485] Compounds of formula (XIV) are commercially available or may be
prepared by methods known in the literature or processes known to those
skilled in the art.

[0486] Compounds of formula (Ic) may be prepared according to reaction
scheme 25 by reacting compounds of formula (IVb) with a base such as
sodium hydride or potassium tertbutoxide or potassium
hexamethyldisilazane in a suitable solvent such as THF or DMSO (suitably
at room temperature or reflux). Compounds of formula (IVb) may be
prepared by reacting compounds of formula (Vd) with acetic acid
derivatives (VI) in the presence of a coupling reagent such as DCC or
EDC/HOBT or COMU and a base such as triethylamine in a suitable solvent
such as acetonitrile (suitably at room temperature). Compounds of formula
(Vd) may be prepared by reacting compounds of formula (V) with
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane in the
presence of an inorganic base such as potassium acetate and a catalyst
(such as Pd(dppf)Cl2) in a suitable solvent such as 1,4-dioxane
(suitably at 100° C.).

##STR00031##

[0487] Alternatively, compounds of formula (IV), wherein R6 is
defined as chloro (formula (IVe)), may be prepared according to reaction
scheme 26 by reacting compounds of formula (IVf), wherein R6 is H,
with N-chlorosuccinimide (NCS) (commercially available) in a suitable
solvent such as chloroform (suitably at room temperature).

##STR00032##

[0488] Compounds of formula (IVf) may be prepared according Scheme 25.

[0489] Further details for the preparation of compounds of formula (I) are
found in the Examples section hereinafter.

[0490] The compounds of the invention may be prepared singly or as
compound libraries comprising at least 2, for example 5 to 1,000
compounds, and more preferably 10 to 100 compounds. Libraries of
compounds of the invention may be prepared by a combinatorial `split and
mix` approach or by multiple parallel synthesis using either solution
phase or solid phase chemistry, by procedures known to those skilled in
the art. Thus according to a further aspect there is provided a compound
library comprising at least 2 compounds of the invention.

[0491] Those skilled in the art will appreciate that in the preparation of
compounds of formula (I) and/or solvates thereof it may be necessary
and/or desirable to protect one or more sensitive groups in the molecule
or the appropriate intermediate to prevent undesirable side reactions.
Suitable protecting groups for use according to the present invention are
well known to those skilled in the art and may be used in a conventional
manner. See, for example, "Protective groups in organic synthesis" by T.
W. Greene and P. G. M. Wuts (John Wiley & sons 1991) or "Protecting
Groups" by P. J. Kocienski (Georg Thieme Verlag 1994). Examples of
suitable amino protecting groups include acyl type protecting groups
(e.g. formyl, trifluoroacetyl, acetyl), aromatic urethane type protecting
groups (e.g. benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic
urethane protecting groups (e.g. 9-fluorenylmethoxycarbonyl (Fmoc),
t-butyloxycarbonyl (Boc), isopropyloxycarbonyl, cyclohexyloxycarbonyl)
and alkyl or aralkyl type protecting groups (e.g. benzyl, trityl,
chlorotrityl).

[0492] The synthesis of the target compound is completed by removing any
protecting groups, which are present in the penultimate intermediate
using standard techniques, which are well-known to those skilled in the
art. The final product is then purified, as necessary, using standard
techniques such as silica gel chromatography, HPLC on silica gel, and the
like or by recrystallization.

[0493] Various intermediate compounds used in the above-mentioned process,
including but not limited to certain compounds of formulae (IV), (V) and
(VIII) constitute a further aspect of the present invention.

[0501] The compounds and processes of the present invention will be better
understood in connection with the following examples, which are intended
as an illustration only and not limiting the scope of the invention.
Various changes and modifications to the disclosed embodiments will be
apparent to those skilled in the art and such changes and modifications
including, without limitation, those relating to the chemical structures,
substituents, derivatives, formulations and/or methods of the invention
may be made without departing from the spirit of the invention and the
scope of the appended claims.

[0502] Regardless of how the preparation of compounds are represented in
the present specification no inference can be drawn that particular
batches (or mixtures of two or more batches) of intermediates were used
in the next stage of the preparation. The examples and intermediates are
intended to illustrate the synthetic routes suitable for preparation of
the same, to assist the skilled persons understanding of the present
invention.

[0503] Where reference is made to the use of a "similar" procedure, as
will be appreciated by those skilled in the art, such a procedure may
involve minor variation, for example reaction temperature,
reagent/solvent amount, reaction time, work-up conditions or
chromatographic purification conditions.

[0514] Copper(II) acetate (6.57 g, 36.2 mmol) was added to a solution of
4-bromophenylboronic acid (9.68 g, 48.2 mmol), ethyl
3-(acetylamino)-1H-pyrrole-2-carboxylate (Intermediate 1) (4.73 g, 24.11
mmol) and pyridine (3.9 mL, 48.3 mmol) in DCM (100 mL) at RT. The
reaction mixture was stirred for 48 h before 4-bromophenylboronic acid
(9.68 g, 48.2 mmol), copper(II) acetate (6.57 g, 36.2 mmol) and pyridine
(3.9 mL, 48.3 mmol) were added again in the same order. The mixture was
stirred for another 24 h. All the reactants were added again and the
mixture stirred for another 15 h. The reaction mixture was then washed
respectively with 1N HCl, water and brine. The combined organic layers
were dried over Na2SO4, filtered and concentrated under reduced
pressure. The crude was then purified by chromatography on an Isco
Companion RF. The sample was loaded on 340 g Biotage SNAP silica (Si)
column then the purification was carried out using eluting with
cyclohexane/EtOAc 100/0 to 60/40. The appropriate fractions were combined
and concentrated in vacuo to give the required product ethyl
3-(acetylamino)-1-(4-bromophenyl)-1H-pyrrole-2-carboxylate (7.91 g, 22.52
mmol, 93% yield) as a colourless oil which solidified. LCMS: (M+H).sup.+:
351, 353; Rt: 3.26 min.

[0558] Method A: Copper(II) acetate (1.018 g, 5.61 mmol) was added to a
solution of [4-(methyloxy)phenyl]boronic acid (0.852 g, 5.61 mmol),
pyrrole (1 g, 5.10 mmol) and pyridine (0.617 mL, 7.65 mmol) in DCM (25
mL) at RT. The reaction mixture was stirred for 18 h and monitoring of
the reaction by LCMS showed the reaction was incomplete with SM
remaining. [4-(methyloxy)phenyl]boronic acid (0.852 g, 5.61 mmol),
copper(II) acetate (1.018 g, 5.61 mmol) and pyridine (0.617 mL, 7.65
mmol) were added again in the same order and the mixture was stirred
another 24 h. Monitoring of the reaction by LCMS showed the reaction was
incomplete with SM remaining and all the reactants were added again every
day for 7 days. The reaction mixture was concentrated to dryness and the
resulting solid was taken up in EtOAc and filtered through Celite. The
filtrate was then washed respectively with 1N HCl and brine. The organic
layers was dried over Na2SO4, filtered and concentrated under
reduced pressure. The crude was then purified by chromatography on a Isco
Companion RF. The sample was loaded on 50 g Biotage SNAP silica column
then the purification was carried out using a cyclohexane/AcOEt 100/0 to
50/50. The appropriate fractions were combined and concentrated in vacuo
to give the required product ethyl
3-(acetylamino)-1-[4-(methyloxy)phenyl]-1H-pyrrole-2-carboxylate (1.05 g,
3.47 mmol, 68.1% yield) as an orange solid. LCMS: (M+H).sup.+: 303; Rt:
3.13 min.

[0559] Method B: Copper(II) acetate (1.018 g, 5.61 mmol) was added to a
solution of [4-(methyloxy)phenyl]boronic acid (0.852 g, 5.61 mmol), ethyl
3-(acetylamino)-1H-pyrrole-2-carboxylate (Intermediate 1) (1 g, 5.10
mmol) and pyridine (0.617 mL, 7.65 mmol) in DCM (25 mL) at RT. The
reaction mixture was stirred for 18 h and [4-(methyloxy)phenyl]boronic
acid (0.852 g, 5.61 mmol), copper(II) acetate (1.018 g, 5.61 mmol) and
pyridine (0.617 mL, 7.65 mmol) were added again in the same order. The
mixture was stirred another 24 h and all the reactants were added again
every day for 7 days (7.7 equiv. in total). The reaction mixture was
concentrated to dryness and the resulting solid was taken up in EtOAc and
filtered through Celite. The filtrate was then washed respectively with
1N HCl and brine. The organic layers was dried over Na2SO4,
filtered and concentrated under reduced pressure. The crude was then
purified by chromatography on silica gel eluting with cyclohexane/EtOAc
100/0 to 50/50. The appropriate fractions were combined and concentrated
in vacuo to give the required product ethyl
3-(acetylamino)-1-[4-(methyloxy)phenyl]-1H-pyrrole-2-carboxylate (1.05 g,
3.47 mmol, 68.1% yield) as an orange solid. LCMS: (M+H).sup.+: 303; Rt:
3.13 min.

[0560] Intermediates 21 to 29 of formula (VIII), wherein R3 is H,
were prepared by methods analogous to that described for Intermediate 20
from Intermediate 1 using the appropriate boronic acid.

[0562] To a solution of ethyl
3-(acetylamino)-1-[4-(methyloxy)phenyl]-1H-pyrrole-2-carboxylate
(Intermediate 20) (3.26 g, 10.78 mmol) in tetrahydrofuran (THF) (100 mL)
at RT was added NCS (1.512 g, 11.32 mmol). The mixture was stirred at RT
for 18 h before being concentrated to dryness. The mixture was taken up
in DCM, washed with water, dried over Na2SO4, filtered and
concentrated under reduced pressure. The crude product was then purified
by chromatography on an Isco Companion RF. The sample was loaded on 100 g
Biotage SNAP silica column then the purification was carried out using a
cyclohexane/EtOAc 95/5 to 70/30. The appropriate fractions were combined
and concentrated in vacuo to give the required product ethyl
3-(acetylamino)-5-chloro-1-[4-(methyloxy)phenyl]-1H-pyrrole-2-carboxylate
(3.12 g, 9.26 mmol, 86% yield) as a yellow oil. LCMS: (M+H).sup.+: 337;
Rt: 3.41 min.

[0563] Intermediates 31 to 39 of formula (VIII), wherein R3 is H and
R6 is Cl, were prepared by methods analogous to that described for
Intermediate 30 using NCS.

[0578] To a solution of ethyl
3-[(cyanoacetyl)amino]-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-1H-pyrrole-2-carboxylate (Intermediate 57) (10 g, 23.63 mmol) in
THF (150 ml) was added sodium hydride (2.362 g, 60% suspension in oil,
59.1 mmol). The reaction mixture was stirred at 45° C. for 54
hours and to complete the reaction sodium hydride (2.362 g, 60%
suspension in oil, 59.1 mmol) was added again and the reaction mixture
was stirred at 45° C. for another 16 hours. The reaction was
concentrated to dryness after quenching with MeOH. After acidification
with 1N HCl, the resulting precipitate was filtered off and dried under
vacuum to give a mixture of pinacol boronate and boronic acid (1:1
mixture) (8 g, 80% yield). The solid was used without further
purification. LCMS: (M+H).sup.+: 378; Rt: 2.69 min.

[0582] Intermediates 60 and 61 of formula (V), wherein R3 and R4
are both H and R6 is Cl, were prepared by methods analogous to that
described for Intermediate 59 from ethyl
3-amino-1-(4-bromophenyl)-5-chloro-1H-pyrrole-2-carboxylate (Intermediate
9) using the appropriate potassium trifluoroborate.

[0589] Intermediates 65 and 66 of formula (V), wherein R3 and R4
are both H and R6 is chlorine, were prepared by methods analogous to
that described for Intermediate 64 from ethyl
3-amino-1-(4-bromophenyl)-5-chloro-1H-pyrrole-2-carboxylate (Intermediate
9) using the appropriate boronic acid.

[0595] Intermediates 69 to 75 of formula (IV), wherein R3 and R4
are both H and R1 is cyano, were prepared by methods analogous to
that described for Intermediate 68 using the appropriate Intermediate.
HATU was used for Intermediate 74 instead of EDC/HOBT

[0597] To a solution of ethyl
3-[(cyanoacetyl)amino]-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl]-1H-pyrrole-2-carboxylate (Intermediate 57) (3.45 g, 8.15 mmol) in
THF (50 mL) was added NCS (1.197 g, 8.97 mmol). The reaction mixture was
stirred 2 h at RT then overnight at 50° C. The reaction mixture
was concentrated in vacuo, taken in DCM (200 mL) and washed with water
then brine. The organic layer was dried over anhydrous Na2SO4,
filtered and concentrated in vacuo. The product was purified by
chromatography on an Isco Companion. The sample was loaded on 50 g
Biotage silica (Si) column then the purification was carried out using
Cyclohexane/EtOAc 100/0 to 60/40. The appropriate fractions were combined
and concentrated in vacuo to give ethyl
5-chloro-3-[(cyanoacetyl)amino]-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl]-1H-pyrrole-2-carboxylate (2.45 g, 5.35 mmol, 65.7% yield)
as a white foam. LCMS: (M-H).sup.-: 456; Rt: 3.98 min.

[0599] Ethyl
5-chloro-3-[(cyanoacetyl)amino]-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro-
lan-2-yl)phenyl]-1H-pyrrole-2-carboxylate (Intermediate 76) (300 mg, 0.655
mmol), 4-bromothiophene-2-carbonitrile (160 mg, 0.85 mmol), 1.0M solution
of Na2CO3 (1.3 mL, 1.3 mmol) in water and Pd(PPh3)4
(7.57 mg, 6.55 μmol) were mixed together in 1,4-dioxane (7 mL). The
reaction vessel was sealed and heated in a Biotage Initiator to
130° C. for 10 min. Monitoring of the reaction by LC/MS showed the
reaction was incomplete with SM remaining. The reaction mixture was then
heated to 130° C. for another 5 min before being concentrated in
vacuo after addition of EtOH. DCM was added to the residue which was
filtered then directly purified by chromatography on silica gel eluting
with cyclohexane/EtOAc 100/0 to 70/30. The appropriate fractions were
collected and concentrated in vacuo to give ethyl
5-chloro-3-(2-cyanoacetamido)-1-(4-(5-cyanothiophen-3-yl)phenyl)-1H-pyrro-
le-2-carboxylate (120 mg, 42% yield). LCMS: (M-H).sup.-: 437; Rt: 3.59
min.

[0600] Intermediates 78 to 87 of formula (IV), wherein R3 and R4
are both H, R6 is Cl and R1 is cyano, were prepared by methods
analogous to that described for Intermediate 77 from Intermediate 76
using the appropriate bromo derivative.

[0602] To a solution of ethyl
1-(4-bromophenyl)-5-chloro-3-[(cyanoacetyl)amino]-1H-pyrrole-2-carboxylat-
e (Intermediate 10) (500 mg, 1.218 mmol) and
2-chloro-6-methoxyphenylboronic acid (681 mg, 3.65 mmol) were added
Pd(PPh3)4 (28.1 mg, 0.024 mmol) and Na2CO3 (3.65 mL,
3.65 mmol) 1M in water in 1,4-dioxane (5 mL). The reaction vessel was
sealed and heated in Biotage Initiator to 120° C. for 5 min. The
reaction mixture was concentrated in vacuo, taken in DCM (25 mL) and
washed with water. The organic layer was dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. The residue was
loaded on 10 g Biotage silica (Si) column then the purification was
carried out using a cyclohexane/EtOAc 100/0 to 80/20 gradient. The
appropriate fractions were combined and concentrated in vacuo to give
ethyl 5-chloro-1-[2'-chloro-6'-(methyloxy)-4-biphenylyl]-3-[(cyanoacetyl)-
amino]-1H-pyrrole-2-carboxylate (170 mg, 30% yield) as a yellow amorphous
solid. LCMS: (M+H).sup.+: 472; Rt: 3.97 min.

[0603] Intermediates 89 to 94 of formula (IV), wherein R3 and R4
are both H, R6 is Cl and R1 is cyano were prepared by methods
analogous to that described for Intermediate 88 from Intermediate 10
using the appropriate boronic acid derivative.

[0605] To a solution of ethyl
5-chloro-3-[(cyanoacetyl)amino]-1-[5'-methyl-2'-(methyloxy)-4-biphenylyl]-
-1H-pyrrole-2-carboxylate (Intermediate 94) (340 mg, 0.752 mmol) in DMSO
(1 mL) was added dropwise potassium tert-butoxide (1.505 mL, 1M in THF,
1.505 mmol). The yellow reaction mixture was stirred at room temperature
for 30 min. Water was added before being acidified with 1N HCl to pH 1.
The precipitate was filtered, washed successively with water (5 mL),
CH3CN (5 mL) and Et2O (5 mL) then dried. The product
2-chloro-7-hydroxy-1-[5'-methyl-2'-(methyloxy)-4-biphenylyl]-5-oxo-4,5-di-
hydro-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (220 mg, 0.504 mmol) was
obtained as a beige powder and was used in the next step without further
purification. LCMS: (M+H).sup.+: 406; Rt: 3.02 min

[0608] Intermediates 97 to 127 of formula (IV), wherein R3 is H, were
prepared by methods analogous to that described for Intermediate 96 using
the appropriate carboxylic acid. For Intermediates 102 and 120,
(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeni-
um hexafluorophosphate COMU) was used instead of EDC/HOBT as a coupling
reagent.

[0613] To a solution of {3-[(methyloxy)carbonyl]phenyl}acetic acid
(prepared by methods analogous to those described in PCT International
Application WO2005080367, 1 Sep. 2005) (400 mg, 2.060 mmol), in DCM (15
mL) at RT were added pyridine (17 μL, 0.206 mmol) and oxalyl chloride
(2M in DCM, 1.236 mL, 2.472 mmol). The reaction mixture was left stirring
overnight before being evaporated to dryness. Methyl
3-(2-chloro-2-oxoethyl)benzoate (410 mg, 1.928 mmol, 94% yield) was
obtained as a yellow oil which was used in the next step without further
purification.

Intermediate 136

Ethyl 2-(2-chloro-2-oxoethyl)benzoate

##STR00155##

[0615] To a solution of {2-[(ethyloxy)carbonyl]phenyl}acetic acid
(prepared by methods analogous to those described in PCT International
Application WO2005080367, 1 Sep. 2005) (416 mg, 1.998 mmol), in DCM (15
mL) at RT were added pyridine (16 μL, 0.200 mmol) and oxalyl chloride
(2M in DCM, 1.199 mL, 2.398 mmol). The reaction mixture was left stirring
overnight before being evaporated to dryness. Ethyl
2-(2-chloro-2-oxoethyl)benzoate (460 mg, 2.030 mmol, 102% yield) was
obtained as a yellow oil, which was used in the next step without further
purification.

[0624] To a solution of ethyl
3-(acetylamino)-1-{4-[(ethyloxy)carbonyl]phenyl}-1H-pyrrole-2-carboxylate
(Intermediate 141) (620 mg, 1.800 mmol) in ethanol (50 mL) was added
concentrated HCl (0.191 mL, 6.30 mmol) and the reaction mixture was
stirred at reflux for 16 h. After evaporation the residue was taken up in
water and extracted with DCM. The organic layer was washed with a
solution of NaHCO3, dried over Na2SO4, filtered and
evaporated to give ethyl
3-amino-1-{4-[(ethyloxy)carbonyl]phenyl}-1H-pyrrole-2-carboxylate (470
mg, 1.244 mmol, 69.1% yield) as yellow oil. LCMS: (M+H).sup.+: 303; Rt:
3.38 min.

[0628] Method A: To a solution of ethyl
1-(4-bromophenyl)-3-[(cyanoacetyl)amino]-1H-pyrrole-2-carboxylate
(Intermediate 4) (510 mg, 1.36 mmol) in tetrahydrofuran (5 mL) at RT was
added portion-wise sodium hydride (65 mg, 1.625 mmol). After hydrogen
evolution stopped, the reaction mixture was stirred at RT for 18 hours
and at reflux for 24 hours before being cooled down and quenched with
MeOH. The mixture was concentrated to dryness and taken up in MeOH with a
few drops of water and triturated at reflux. After cooling down to RT,
the solid was filtered and the resulting filtrate was concentrated under
reduced pressure to give the desired compound
1-(4-bromophenyl)-7-hydroxy-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-6-
-carbonitrile (330 mg, 1.000 mmol, 74% yield) as an orange solid. 1H
NMR: (DMSO-d6, 400 MHz) δ 9.85 (s, 1H), 7.53 (m, 2H), 7.34 (m, 2H),
7.04 (d, J=3.0 Hz, 1H), 5.92 (d, J=3.0 Hz, 1H). LCMS: (M+H).sup.+: 330,
332; Rt: 2.10 min.

[0629] Method B: To a solution of ethyl
1-(4-bromophenyl)-3-[(cyanoacetyl)amino]-1H-pyrrole-2-carboxylate
(Intermediate 4) (4.5 g, 11.96 mmol) in THF (45 mL) at RT was added
portionwise sodium hydride (60% suspension in oil, 574 mg, 14.35 mmol).
After hydrogen evolution stopped, the reaction mixture was stirred at
reflux for 48 h before being cooled down and quenched with MeOH. The
mixture was concentrated to dryness and taken up in MeOH with a few drops
of water and triturated at reflux. After cooling down to RT, the solid
was filtered to give the desired compound
1-(4-bromophenyl)-7-hydroxy-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-6-
-carbonitrile (3.4 g, 10.30 mmol, 86% yield) as a light yellow solid.
HRMS: calculated for C14H7BrN3O2(M-H).sup.-:
329.9878; found: 329.9843; Rt: 1.96 min.

[0632] Examples 3 to 8 of formula (I), wherein R1 is cyano and
R3, R4, R6 and R7 are all H were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0635] Examples 10 to 19 of formula (I), wherein R1 is cyano and
R3, R4, R6 and R7 are all H, were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0643] Method A: To a solution of ethyl
1-(4-bromophenyl)-5-chloro-3-[(cyanoacetyl)amino]-1H-pyrrole-2-carboxylat-
e (Intermediate 10) (5.66 g, 13.78 mmol) in THF (50 mL) was added sodium
hydride (0.662 g, 16.54 mmol). After hydrogen evolution stopped, the
reaction mixture was stirred at 50° C. during 2 hours. Sodium
hydride (1.2 eq) was added again twice and the mixture was stirred at
50° C. overnight. The mixture was then stirred at RT for two days
before being quenched with 1N HCl. The reaction mixture was dissolved in
EtOAc and the organic layer was concentrated in vacuo. The solid was
triturated in EtOAc and filtered. The product was then purified on a Isco
Companion with the filtrate. The sample was loaded on 120 g AIT silica
(Si) column then the purification was carried out using a DCM/MeOH 100/0
to 80/20 gradient. The appropriate fractions were combined and
concentrated in vacuo to give the required product (2.7 g, 70% yield) as
a orange solid. 1H NMR: (DMSO-d6, 300 Hz) δ 11.60 (br s, 1H),
7.70 (d, J=8.5 Hz, 2H), 7.38 (d, J=8.5 Hz, 2H), 6.30 (s, 1H). LCMS:
(M+H).sup.+: 364, 366; Rt: 2.55 min.

[0647] Examples 25 to 29 of formula (I), wherein R3, R4 and
R7 are all H and R6 is Cl, were prepared by methods analogous
to that described for Example 24 from Example 23 using the appropriate
boronic acid.

[0650] Examples 31 to 35 of formula (I), wherein R1 is cyano and
R3, R4, R6 and R7 are all H were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0660] To a solution of
1-(4-bromophenyl)-7-hydroxy-6-phenyl-1,4-dihydro-5H-pyrrolo[3,2-b]pyridin-
-5-one (Intermediate 18) (200 mg, 0.525 mmol) and (2-hydroxyphenyl)boronic
acid (87 mg, 0.630 mmol) in 1,4-dioxane (5 mL) was added a solution of
Cs2CO3 (513 mg, 1.574 mmol) in water (1 mL). The mixture was
purged with nitrogen and Pd(PPh3)4 (10 mg, 8.65 μmol) was
added. The reaction vessel was sealed and heated in Biotage Initiator at
130° C. for 20 min before being concentrated under reduced
pressure. Water was added and the solid was filtered and discarded. The
aqueous phase was concentrated under reduced pressure, MeOH was added,
and the solution was heated then filtered. The organic phase was
concentrated, a little of MeOH was added then product was filtered and
dried under reduced pressure to give
7-hydroxy-1-(2'-hydroxy-4-biphenylyl)-6-phenyl-1,4-dihydro-5H-pyrrolo[3,2-
-b]pyridin-5-one (36 mg, 0.089 mmol, 17.05% yield) as a light brown solid.
LCMS: (M+H).sup.+: 395; Rt: 2.58 min. HRMS: calculated for
C25H19N2O3 (M+H).sup.+: 395.1396; found: 395.1418;
Rt: 2.37 min

[0667] Examples 44 to 47 of formula (I), wherein R1 is CN and
R3, R4, R6 and R7 are all H, were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0670] Examples 49 to 55 of formula (I), wherein R1 is CN and
R3, R4, R6 and R7 are all H, were prepared by methods
analogous to that described for Example 48 from Intermediate 58 using the
appropriate heteroarylbromide.

[0672] To a mixture of
1-(4-bromophenyl)-7-hydroxy-5-oxo-4,5-dihydro-1H-pyrrolo[3,2-b]pyridine-6-
-carbonitrile (Example 1) (150 mg, 0.454 mmol) and Pd(PPh3)4
(26.3 mg, 0.023 mmol) in a 1,4-dioxane (2.5 mL)/water (1.5 mL) mixture
were added Cs2CO3 (444 mg, 1.363 mmol) and
(1-{[(1,1-dimethylethyl)oxy]carbonyl}-1H-pyrrol-2-yl)boronic acid (128
mg, 0.606 mmol). The reaction mixture was stirred at 150° C. for
15 minutes in a microwave oven Biotage initiator. The mixture was
solubilized in DMF and filtered through a SPE guanidine column. The
filtrate was then evaporated and purified by chromatography on an Isco
Companion RF. The sample was loaded on 25 g Biotage silica (Si) column
then the purification was carried out using a DCM/MeOH 100/0 to 40/60
gradient. The appropriate fractions were combined and concentrated in
vacuo to give the required product
7-hydroxy-5-oxo-1-[4-(1H-pyrrol-2-yl)phenyl]-4,5-dihydro-1H-pyrrolo[3,2-b-
]pyridine-6-carbonitrile (30 mg, 16% yield) as a white solid. LCMS:
(M+H).sup.+: 317; Rt: 2.58 min. HRMS: calculated for
C18H11N4O2 (M-H).sup.-: 315.0882; found: 315.0873;
Rt: 2.01 min.

[0673] Examples 57 and 58 of formula (I), wherein R1 is CN and
R3, R4, R6 and R7 are all H were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0674] Example 59 of formula (I), wherein R1 is CN and R3,
R4, R6 and R7 are all H was prepared by methods analogous
to that described for Example 48 from Intermediate 58 using the
appropriate heteroarylbromide.

[0675] Examples 60 to 65 of formula (I), wherein R1 is CN and
R3, R4, R6 and R7 are all H, were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0676] Example 66 of formula (I), wherein R1 is CN and R3,
R4 and R7 are all H and R6 is Cl was prepared by methods
analogous to that described for Example 24 from Example 23 using the
appropriate boronic acid.

[0677] Examples 67 and 68 of formula (I), wherein R1 is CN and
R3, R4, R6 and R7 are all H, were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0678] Examples 69 and 70 of formula (I), wherein R1 is CN and
R3, R4 and R7 are all H and R6 is Cl were prepared by
methods analogous to that described for Example 24 from Example 23 using
the appropriate boronic acid.

[0679] Examples 71 and 72 of formula (I), wherein R1 is CN and
R3, R4, R6 and R7 are all H, were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0682] Example 74 of formula (I), wherein R1 is CN and R3,
R4, R6 and R7 are all H, was prepared by a method
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0684] To a suspention of
7-hydroxy-1-{4-[2-(methyloxy)-3-pyridinyl]phenyl}-5-oxo-4,5-dihydro-1H-py-
rrolo[3,2-b]pyridine-6-carbonitrile (Example 72) (140 mg, 0.391 mmol) in
DCM (30 mL) at 0° C., was added BBr3 (1.172 mL, 1M in DCM,
1.172 mmol). The reaction was stirred at RT for 24 h before being
quenched cautiously with EtOH (30 ml). Water (10 ml) was then added and
the mixture was heated to reflux for 48 h. After cooling to RT, the
reaction mixture was filtered and washed with acetonitrile. Trituration
in diethyle ether and drying gave
7-hydroxy-1-[4-(2-hydroxy-3-pyridinyl)phenyl]-5-oxo-4,5-dihydro-1H-pyrrol-
o[3,2-b]pyridine-6-carbonitrile (120 mg, 0.349 mmol, 89% yield) as a cream
powder. LCMS: (M+H).sup.+: 345; Rt: 3.18 min. HRMS: calculated for
C19H11N4O3 (M-H).sup.-: 343.0831; found: 343.0833;
Rt: 1.64 min.

[0685] Examples 76 and 77 of formula (I), wherein R1 is CN and
R3, R4 and R7 are all H and R6 is Cl, were prepared
by methods analogous to that described for Example 24 from Example 23
using the appropriate boronic acid.

[0690] Examples 80 to 82 of formula (I), wherein R1 is a
(4-cyanophenyl) and R3, R4, R6 and R7 are all H, were
prepared by methods analogous to that described for Example 39 from
Intermediate 16 using the appropriate boronic acid in dioxane/water at
110° C.

[0691] Examples 83 and 84 of formula (I), wherein R1 is CN and
R3, R4 and R7 are all H and R6 is Cl, were prepared
by methods analogous to that described for Example 24 from Example 23
using the appropriate boronic acid.

[0692] Examples 85 and 86 of formula (I), wherein R1 is cyano and
R3, R4, R6 and R7 are all H, were prepared by methods
analogous to that described for Example 2 from Example 1 using the
appropriate boronic acid.

[0693] Examples 87 to 92 of formula (I), wherein R1 is CN and
R3, R4, R6 and R7 are all H, were prepared by methods
analogous to that described for Example 48 from Intermediate 58 using the
appropriate heteroarylbromide.

[0700] Example 96 of formula (I), wherein R1 is CN and R3,
R4 and R7 are all H and R6 is Cl, was prepared by methods
analogous to that described for Example 95 from Intermediate 76 using the
appropriate bromo derivative.

[0725] Human recombinant AMPK (Invitrogen #PV4673 & #PV4675) is used in a
FRET assay format (Z'Lyte--Invitrogen). Assay conditions are as follow:
ATP 100 μM, peptide (Invitrogen #PR8650) 2 μM, 1% final DMSO in
Z'Lyte kinase buffer. Reaction is initiated by addition of 0.2-0.8 ng of
AMPK and incubated for 1-hour @ 30° C. A further 1-hour incubation
@ 30° C. with the development reagent (Invitrogen #PR5194) is
performed. FRET signal is then measured and converted to "% peptide
phosphorylation" according to Z'Lyte given calculation procedure.
Evaluation of compounds is carried out using concentration-response
curves. Final data are expressed in "% activation" calculating the ratio
of "% peptide phosphorylation" between compound-condition and
basal-condition. Alternatively pEC200 (-Log(compound concentration
leading to a 2-fold AMPK activity increase)) is produced through fitting
of the concentration-response curves. All data are means of at least 2
independent experiments.

[0726] The compounds of Examples 1 to 34 and 36 to 76 were tested in the
assay described above and gave pEC200 values of greater than 4.0.

[0727] In one aspect, the compounds of the invention give a pEC200
value of ≧5.0 when tested in this assay. In a further aspect, the
compounds of the invention give a pEC200 value of ≧6.0 when
tested in this assay. In a further aspect, the compounds of the invention
give a pEC200 value of ≧7.0 when tested in this assay.

[0728] The compounds of Examples 35 and 77 to 169 were tested in the assay
described above and gave average pEC50 values of greater than 4.5.

[0729] In one aspect, the compounds of the invention give average
pEC50 values of ≧5.0 when tested in this assay. In a further
aspect, the compounds of the invention give average pEC50 values of
≧6.0 when tested in this assay. In a further aspect, the compounds
of the invention give average pEC50 values of ≧7.0 when
tested in this assay.

[0730] For instance, Example compounds 5 and 72 gave an average
pEC200 value of 5.8 and 5.6 respectively.

[0731] The following compounds were also prepared and when tested by the
above described in vitro assay for AMPK activity were found to exhibit an
average pEC200 value of less than 4 or a PEC50 value of less
than 4.5.